This proposal focuses on lung disease in anti-RNP autoimmunity, the leading cause of death in Mixed Connective Tissue Disease, and a significant clinical issue in RNP+ lupus. Based on preliminary data in a murine model of anti-RNP autoimmunity and human studies, we hypothesize that a subset of CD11c+ CD11bhigh CD103- myeloid dendritic cells acting through TLR-inducible TRIF-mediated pathways play a central role in the pathogenesis of anti-RNP autoimmune lung disease. In this proposal, we will test this hypothesis with studies in animal models. In Aim 1, we will assess the relevance of TRIF to anti-RNP lung disease by direct immunization and adoptive transfer studies with TRIF-/- mice. In Aim 2, we will assess the relevance of CD11b+ mDC's to anti-RNP lung disease using depletion studies with clodronate or antibodies to DC surface markers, and we will test the therapeutic efficacy of a novel immunosuppressive therapeutic agent that targets CD11b-expressing cells in anti-RNP lung disease. These studies will lead to improved understanding and potentially to novel treatment approaches for a spectrum of autoimmune disease for which current treatments have not been efficacious.